How Diabetes, Like Sugar, May Fuel Viral Growth
August 24, 2020
In response to yesterday's newsletter on sugar, one of you asked:
Could this be why people with diabetes seem susceptible? I'm guessing if they have elevated blood sugar levels this could make viral replication stronger?
Diabetics do not seem to have an increased incidence of COVID-19, but those who get COVID-19 have much worse outcomes. These include a higher risk of hospitalization and a higher risk of admission to the ICU. Among those hospitalized, diabetics are 2.5 times as likely to die. They also have 2.3 times the risk of acute respiratory distress, 2.4 times the risk of acute heart injury, 4.9 times the risk of acute kidney injury, and 3.8 times the risk of septic shock. Among diabetics, those with poorly controlled blood glucose have ten times the mortality rate as those with well controlled blood glucose (11% vs. 1.1%).
I haven't been able to find any studies addressing whether diabetics have an increased viral load. However, we know in the context of COVID-19 that a higher viral load is correlated with a greater risk of dying. We also know that when isolated cells are incubated with diabetic concentrations of glucose, it increases the replication of influenza virus.
There are many reasons why diabetics may have more severe COVID-19 outcomes. These include impaired immune responses that give the virus a better chance of thriving, dysregulated immune responses that increase the risk of a cytokine storm, poor blood vessel function increasing the risk of clotting, and poor airway function increasing the risk of respiratory distress. Diabetes may also increase the production of ACE2, which serves as the entryway of the virus into our cells.
However, there are also important ways that diabetes alters the pentose phosphate pathway and the supply of glutathione, topics we covered yesterday, that would be expected to fuel viral growth. These appear to be very underappreciated, because recent reviews (for example, here and here) don't mention them at all.
Yesterday, we covered these effects of sugar:
The fructose component of sugar enters the non-oxidative arm of the pentose phosphate pathway, bypassing the oxidative arm. This allows it to fuel the production of ribose 5-phosphate, needed to replicate the viral genome, without generating as much NADPH, needed to recycle glutathione, which has antiviral properties.
Whereas glucose is “pulled” into these pathways according to the cell's need for it, fructose “pushes” these pathways forward according to its own supply. This leads to an excess supply of ribose 5-phosphate that lies latent, waiting for a virus to take advantage of it.
Although the glucose component of sugar can fuel the oxidative arm of the pathway, allowing the production of NADPH, this NADPH tends to get sucked into fatty acid synthesis during sugar-feeding, leaving little left over to recycle glutathione.
Thus, sugar leads to the execution of the virus's “preferred” program of carbohydrate metabolism: excess production of ribose for viral replication, without as much recycling of glutathione, which prevents viral replication.
Now let's take a look at what we know about diabetes:
Diabetes involves a deficit of insulin signaling. Either the insulin itself is deficient, as in type 1 diabetes, or the cells are resistant to its signal, as in type 2 diabetes.
Since insulin stimulates the synthesis of glutathione, diabetics have lower glutathione levels, and these are reversed with the administration of insulin.
Through multiple mechanisms I described in my Masterclass With Masterjohn Energy Metabolism class, insulin increases the rate at which glucose is burned for energy in a pathway known as glycolysis. Most importantly, insulin stimulates an enzyme known as glyceraldehyde 3-phosphate dehydrogenase, abbreviated GAPDH and pronounced (Gap D-H), and this enzyme appears to be impaired in diabetes. GAPDH represents a gatekeeper that, when turned on, shuttles sugars away from the non-oxidative arm of the pentose phosphate pathway that leads to the production of ribose 5-phosphate.
Probably as a result of impaired glycolysis, diabetics have increased activity of both the oxidative and non-oxidative arms of the pentose phosphate pathway. As a result, they have increased levels of ribose in their blood, which would be expected to fuel the replication of viruses.
Although diabetics have increased activity of the oxidative arm of the pathway, which could increase NADPH production, they also have increased activity of a different pathway known as the “polyol” pathway. This converts sugars to sugar alcohols when sugars build up, and consumes NADPH. This means that there may not be any extra NADPH left over to improve glutathione recycling. In fact, diabetics have lower glutathione levels and lower rates of glutathione recycling.
Diabetics with poor COVID-19 outcomes have elevated levels of ribose 5-phosphate in their serum. The authors of this paper suggested this might be a result of hemolysis, where red blood cells split apart, since this would leak ribose 5-phosphate from the cells into the serum. However, we already know from existing studies that diabetics have increased ribose production.
So, here is how diabetes and sugar consumption compare and contrast:
Whereas fructose is biased towards producing ribose 5-phosphate because it bypasses the oxidative part of the pathway that generates NADPH, diabetics make more ribose 5-phosphate because lack of insulin signaling slows down glycolysis. Glucose thus produces ribose 5-phosphate instead of being burned for energy.
Whereas fructose is unable to enter the oxidative part of the pathway to generate NADPH under most circumstances and it causes NADPH to be depleted in the production of fatty acids, diabetics have their NADPH depleted in the production of sugar alcohols (type 2 diabetics, specifically, may also have increased fatty acid synthesis, adding another parallel to sugar consumption).
Whereas fructose bypassing the production of NADPH means less glutathione can be recycled, diabetes represents a double whammy against glutathione: high levels of glucose resulting from impaired glycolysis generate sugar alcohols, taking NADPH away from glutathione recycling; and low insulin signaling directly impairs the synthesis of glutathione.
Here's the real kicker, though: sugar consumption is likely to fuel viral growth even worse in a diabetic than in a non-diabetic. Why? Because insulin turns on GAPDH, which drives fructose down the glycolytic pathway to be burned for energy. If GAPDH activity is impaired, as it is in diabetes, fructose enters glycolysis as glyceraldehyde 3-phosphate, but the glyceraldehyde 3-phosphate, rather than being burned for energy, accumulates. This would increase the rate at which it pushes forward the the production of ribose 5-phosphate for viral replication.
In Plainer Language
To put this in plainer language:
Fructose, even in a healthy person, bypasses the production of the antiviral glutathione and pushes forward the production of ribose 5-phosphate, which fuels the replication of viruses.
This is in contrast to glucose, which is sucked into these pathways on an as-needed basis.
In diabetes, low insulin signaling compromises the production of the antiviral glutathione. It leads to poor clearance of glucose, which causes the production of sugar alcohols, which hurts the recycling of glutathione. Poor clearance of sugars also leads to excess production of ribose 5-phosphate to fuel viral replication.
The combination of low glutathione and high ribose 5-phosphate means less antiviral defense and more fuel for the fire of viral growth.
Fructose intake would fuel ribose 5-phosphate production even more in diabetes, because sugars are poorly cleared in diabetes.
The Bottom Line
Limiting natural sugars to 2-3 pieces of fruit per day and strictly limiting added fructose-containing sugars is likely to limit viral growth, and that may help limit the severity of COVID-19. This has not been tested in human studies, but is predicted from biochemistry.
The relevant sugars are any which contain fructose. These include sucrose, which is table sugar; high-fructose corn syrup; and most natural sugars, except those used in low-FODMAP diets.
This doesn't mean that COVID-19 isn't dangerous if one limits sugars. Even if this hypothesis proves to be correct, it simply means that sugar intake could be fuel for the fire, not that the fire poses no danger without the sugar.
Diabetes is strongly correlated with poor COVID-19 outcomes, and the difference between poorly controlled and well controlled glucose is dramatic. Working with a health care practitioner to maintain tight glucose control, and doubling down on the moderation of fruit and limitation of added sugar, may help reduce this risk.
Again, this is predicted from the biochemistry, not shown to be the case in human studies. Still, there are many reasons to limit sugar intake, and it may well help. In fact, it may turn out to be among the most helpful things one can do with one's diet.
Stay safe and healthy,
Chris
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*Footnotes
* The term “preprint” is often used in these updates. Preprints are studies destined for peer-reviewed journals that have yet to be peer-reviewed. Because COVID-19 is such a rapidly evolving disease and peer-review takes so long, most of the information circulating about the disease comes from preprints.